Project Summary/Abstract A reduction in the vasoconstrictive responsiveness of the afferent arteriole relative to perfusion pressure is implicated in the progression of glomerular injury in diabetes, some forms of hypertension and chronic kidney diseases involving the loss of functional nephrons. A reduction of the vasoconstrictive responsiveness of the afferent arteriole raises afferent blood flow and intraglomerular pressure which is believed to increase mechanical stress (cyclic stretch and fluid flow shear stress) on the glomerular cells. In response to cyclic stretch, mesangial cells increase deposition of extracellular matrix (ECM) components and podocytes may detach from the glomerular capillary. In response to increased shear stress, vascular endothelial cells increase production of inflammatory markers. These results collectively indicate that a reduced vasoconstrictive responsiveness of the afferent arteriole relative to perfusion pressure causes injury of glomerular cells by increasing shear stress on and cyclic stretch of the glomerular capillary walls. Although mechanical stress- induced glomerular injury is a generally accepted concept in kidney disease research, the actual magnitudes of mechanical stress, in particular shear stress and hoop stress resulting from an attenuated afferent arteriole vasoconstrictive response, are unknown. The overall aim of this proposal is to use multiscale mathematical modeling to estimate the magnitudes of shear stress and capillary wall stretch in the glomerular capillary network as a result of decreased afferent arteriole vasoconstrictive responsiveness. We will develop a ?glomerular network model? that calculates flows through the capillaries of an actual, anatomically-accurate glomerular microvascular network. A feedback model of afferent arteriole resistance will be integrated with the glomerular network model to represent the complex dynamics of renal autoregulation in our model. Additionally, we will develop a computational fluid dynamics (CFD) model of a single glomerular capillary, taking into account the dynamics arising from elastic red blood cell structures flowing in a permeable channel. Taking a multiscale mathematical modeling approach, for each capillary segment of the glomerular network model, output of the glomerular network model will be mapped to parameters in the CFD capillary model to calculate shear stresses on the vessel walls. The mechanical stresses calculated using this approach will be compared to experimental parameters of previous cell studies to determine the risk of glomerular cell injury with and without the pathological hemodynamic conditions arising from reduction in afferent arteriole vasoconstrictive responsiveness. This work will serve as a basis for a glomerular injury risk index in pathological renal hemodynamic conditions and will inform the design of ?glomerulus-on-a-chip? microphysiological systems. Mechanical forces are known to crucially affect the efficacy of these systems as models of disease and as drug testing platforms; thus, the proposed project will contribute to development and establishment of these systems for these contexts of use.